Cytomegalovirus (CMV) is a life-and sight-threatening disease in immunocompromised individuals (i.e. AIDS and organ transplant patients). Exclusive of the MHC murine CMV (MCMV) resistance in inbred mice is controlled by a single autosomal dominant gene. Cmv1. Resistant C57BL/6J (B6) mice express the Cmvl allele that directs natural killer (NK) cell protective immunity, in contrast to MCMV susceptible BALB/c mice (CMV1). Importantly, Cmv1 is linked to the natural killer gene complex on mouse chromosome 6, a genomic region that encodes many NK cell receptors that regulate NK cell recognition of target cells. the long term objective of this proposal is to identify and characterize Cmv1 and to understand Cmv1 regulated NK cell immunity mechanistically. To achieve this objective, previously identified NKC markers will be used to identify additional B6- NKC-derived genomic clones to facilitate chromosome "walking" toward Cmvl (specific aim #1). Genomic clones that align to the Cmvl genetic interval will be screened for NK cell expressed sequences by PCR and/or exon trapping, to select cDNA clones. Hence, scrutiny of CDNA strain and tissue expression profiles and sequence information will be used to discern a putative Cmv1 candidate cDNA clone(S) (Specific aim #2). Subsequently, a candidate Cmv1 transgene will be introduced into the BALB/c mouse germline. To verify Cmv1 authenticity, MCMW resistance in Cmvl transgene expressing BALB/c mice will be assessed by monitoring post-infection spleen viral titers, since splenic viral replication has been directly correlated with survival (Specific aim #3).